Immunologic resilience and COVID-19 survival advantage

Lee, Grace C.; Restrepo, Marcos I.; Harper, Nathan; Manoharan, Muthu Saravanan; Smith, Alisha M.; Meunier, Justin A.; Sanchez-Reilly, Sandra; Ehsan, Aamir; Branum, Anne P.; Winter, Caitlyn; Winter, Lauryn; Jimenez, Fabio; Pandranki, Lavanya; Carrillo, Andrew; Perez, Graciela L.; Anzueto, Antonio; Trinh, Hanh; Lee, Monica; Hecht, Joan M.; Martinez, Celida; Sehgal, Raj T.; Cadena, Jose; Walter, Elizabeth A.; Oakman, Kimberly; Benavides, Raymond; Pugh, Jacqueline A.; Letendre, Scott; Steri, Maristella; Orrù, Valeria; Fiorillo, Edoardo; Cucca, Francesco; Moreira, Alvaro G.; Zhang, Nu; Leadbetter, Elizabeth; Agan, Brian K.; Richman, Douglas D.; He, Weijing; Clark, Robert A.; Okulicz, Jason F.; Ahuja, Sunil K.

Background The risk of severe COVID-19 varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). Objective To examine whether deficits in IR that antedate or are induced by SARS-CoV-2 infection independently predict COVID-19 mortality. Methods IR levels were quantified with two novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n=522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n=13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to clinical outcomes. Results IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection associated with underrepresentation of IHG-I (21%) vs. overrepresentation (77%) of IHG-II or IHG-IV, especially in males vs. females (P<0.01). Presentation with IHG-I associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. Conclusion Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19. Clinical implications Biomarkers tracking immunologic resilience may have broad prognostic utility, as they associated with longevity, as well as resistance to a progressive disease course during SARS-CoV-2, influenza, or HIV infection.